Ion channels lie at the heart of the dynamics of excitable cells and control the action potential responsible for the beat of a cardiac cell or the firing of a synapse. Traditionally, calcium has been the most studied ion in the intracellular space, and as a result a good deal is understood about calcium ion dynamics, regulation and impact on the cell. While it is generally believed that sodium is essential to the function of excitable cells, its role is not as well understood. Sodium channels occur at sites of action potential generation in neurons and are responsible for the upstroke of the action potential in cardiac cells. Sodium channelopathies are known to be responsible for major classes of disease, including epilepsy and hypertension, as well as leading to potentially fatal arrhythmias in Long QT syndrome. In addition, calcium dynamics are often dependent upon sodium, through the sodium/calcium exchanger. The exchanger is responsible for the rapid export of calcium from the cell and is driven by the transmembrane sodium gradient. While channel labeling studies have elucidated the location of sodium channels, little is known about the function, dynamics and impact of sodium channels.
There is a wide selection of methods for measuring ion flux in cells including, for example, patch clamping, fluorescent indicator dyes, polymer-based ion-selective nanosensors and dye-loaded liposomes. There are, however, disadvantages to the available methods of ion monitoring. For example, whole-cell patch clamp monitoring which involves contacting cells with a pulled glass capillary to electrically monitor ion channels, can be performed on single cells but not reliably in a high-throughput fashion. Fluorescent ion-indicator dyes while effective for monitoring certain ions, lack selectivity for other physiological ions and are easily photobleached. Ion-selective nanosensors (e.g., probes encapsulated by biologically localized embedding (PEBBLEs)) which comprise a fluorescent indicator dye display fast response time to ions as they diffuse into the polymer matrix, however, the components of the nanosensors, such as the fluorescent dye, are also prone to photobleaching. Dye-loaded liposomes are highly biocompatible due to their lipid construction but are limited in their range of detectable analytes particularly to gases.
New methods are needed for monitoring ion fluctuations in cells that are selective for a particular ionic analyte such as sodium, are biocompatible and have prolonged sensor lifespans. Further, sensors that are small enough to enter the cell but emit a strong enough signal to be measured extracellularly would be highly desired.